Our work on the impact of rare CCR2 variation on atherosclerosis risk is ow published at Genome Medicine

📣 Our new paper on rare 𝘊𝘊𝘙2 variants that offer protection against atherosclerotic cardiovascular disease is now out ‼️

Building on our previous work (summarized here: https://academic.oup.com/eurheartj/article/43/19/1799/6543079), we searched for rare deleterious variants in the gene coding for CCR2, the receptor of CCL2, that governs monocyte recruitment to atherosclerotic plaques and explored associations with lifetime cardiovascular disease risk in 1.5M individuals.

📊 Topline findings

1️⃣ In whole-exome seqeuncing data from the UK Biobank (n=454,775), we found 45 variants in coding regions of the 𝘊𝘊𝘙2 gene that were predicted by computational models to be damaging or loss-of-function (n=787 carriers, all heterozygotes). These individuals were at lower risk of myocardial infarction and coronary artery disease.

2️⃣ One of these missense variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with
👉 lower monocyte count in human carriers
👉 decreased migration towards CCL2 as tested in vitro in human THP-1 CCR2-knockout monocytes transfected with the variant
👉 reduced downstream CCR2-CCL2 signaling activity as tested in vitro in HEK293T cells.
These analyses established M249K as a deleterious missense variant.

3️⃣ In UK Biobank, M249K was associated with lower risk of myocardial infarction, coronary artery disease, a combined atherosclerosis endpoint, and severe atherosclerosis in >1 vascular beds, despite it not being associated with any known vascular risk factors

4️⃣ Pooling 7 cohorts of >1.5M individuals (UK Biobank, TOPMed, deCODE, PMBB, MGB, MVP, Geisinger) totalling 1314 heterozygous M249K carriers, we found associations with a lower lifetimes odds of
👉 myocardial infarction (OR: 0.66, 95% confidence interval [CI]: 0.54–0.81, p = 6.1 E−5)
👉 coronary artery disease (OR: 0.74, 95%CI: 0.63–0.87, p = 2.9 E−4)

5️⃣ In a phenome-wide association study, there was no evidence of a higher risk of infections or all-cause mortality among M249K carriers.

We believe our data to provide further genetic support for the CCL2-CCR2 axis as a potential target for new atheroprotective treatments.

🔗 Link to the paper at Genome Medicine: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-025-01456-2